Nanoshells on polymers

ABSTRACT

Nano-constructs comprising nanoshells and methods of using the nano-constructs for treating or ameliorating a medical condition are provided.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to a method of forming ananoshell on a polymeric material, in particular a biodegradablepolymeric material.

2. Description of Related Art

Nanoshell technology has attracted much attention because of thepotential it offers in therapeutics with or without a therapeuticsubstance. For example, nanoshells have been demonstrated to absorb andconvert light into heat, which can be used to offer local delivery of adrug or local treatment of an injury. Methods of forming nanoshells havebeen focused on forming them on a core material such as nanoparticulateinorganic ceramics or polymers such as polystyrene. For example, U.S.Pat. No. 6,685,986 is directed to a method of forming metal nanoshellsupon a core substrate. The core substrate can be particles of silicondioxide, titanium dioxide, poly(methyl methacrylate) (PMMA),polystyrene, gold sulfide, macromolecules such as dendrimers, andsemiconductors such as Cd Se, Cd S, or GaAs. The particles can furtherhave polyvinyl alcohol (PVA), latex, nylon, Teflon, acrylic, Kevlar,epoxy, glasses (col. 4, line 39 to col. 5, line 33). These coresubstrates, particularly those polymeric core materials, are generallynon-degradable materials.

Therefore, there is a need for forming nanoshells upon a core materialwhich is degradable.

The embodiments described below address the above-identified problems.

SUMMARY

The present invention provides a method of forming nanoshells on apolymeric core substrate. The nanoshell can be a thin layer formed onthe polymeric core material. The nanoshell can have a thickness fromabout 5 nm to about 50 nm, e.g., about 5 nm to about 25 nm. The coresubstrate can have a size between about 100 nm to about 2000 nm, e.g.,between about 100 nm and 50 nm.

The nano-constructs described herein have nanoshells formed on a corematerial. The nanoshells include a metal, carbon, or a conductingpolymer. The nano-constructs can be administered to a target tissue of asubject, which can be human or an animal. An energy source can then beapplied to the nano-constructs. The nano-constructs absorb the energyand then translate the energy into heat, thereby providing therapy tothe subject.

In some embodiments, where the nano-constructs include one or morebioactive agents (e.g., a drug), the nano-constructs can convert energyinto heat so as to cause the bioactive agents to be released. In someembodiments, the nano-construct can include a nanoshell that is porousto the bioactive agent or can be caused to form pores by heat generatedby the interaction of the energy with the nano-construct. Thenano-constructs can be used to treat or to ameliorate a vascularcondition such as atherosclerotic plaque. Other vascular conditions thatcan be treated or ameliorated include, but are not limited to,vulnerable plaque, vascular inflammation, diffuse atheroscleroticdisease, or restenosis.

DETAILED DESCRIPTION

The present invention provides a method of forming nanoshells on apolymeric core substrate. The nanoshell can be a thin layer formed onthe core substrate formed of the polymeric core material. The nanoshellcan have a thickness from about 5 nm to about 50 nm, e.g., about 5 nm toabout 25 nm. The core substrate can have a size between about 100 nm toabout 2000 nm, e.g., between about 100 nm and 150 nm.

The nano-constructs described herein have nanoshells formed on a corematerial. The nanoshells include a metal, carbon, or an electricallyconductive, organic material such as graphite or a conductive polymer.The nano-constructs can be administered to a target tissue of a subject,which can be human or an animal. An energy source can then be applied tothe nano-constructs. The nano-constructs absorb the energy and thentranslate the energy into heat, thereby providing therapy to thesubject.

In some embodiments, where the nano-constructs include one or morebioactive agents (e.g., a drug), the nano-constructs can convert energyinto heat so as to cause the bioactive agents to be released. In someembodiments, the nano-construct can include a nanoshell that is porousto the bioactive agent or can be caused to form pores by heat generatedby the interaction of the energy with the nano-construct.

The nano-constructs can be used to treat or to ameliorate a vascularcondition such as atherosclerotic plaque. Other vascular conditions thatcan be treated or ameliorated include, but are not limited to,vulnerable plaque, vascular inflammation, diffuse atheroscleroticdisease, or restenosis.

In some embodiments, the nanoshells include a metal or an alloy. In someembodiments, the metal or metal alloy can include gold, silver,platinum, palladium, chromium, iridium, biodegradable metals such asiron, iron based alloys, magnesium, magnesium alloys, zinc, calcium,tungsten, alloys based on these metals, or combinations thereof.

In some embodiments, the nanoshells can comprise carbon. In someembodiments, the nanoshells can comprise an electrically conductive,organic material such as graphite or a conductive polymer. Conductivepolymers can be, for example, poly(pyrrole), poly(thiophene),poly(acetylene), poly(aniline), graphite, carbon nanotubes, DNA orcombinations thereof. The term conductive polymer can be usedinterchangeably with the term “conductive polymer.”

The nanoshells have a thickness in the range between about 2 nm andabout 100 nm. Thickness of the shells and the ratio of core to shelldimension is relevant to the frequency of electromagnetic radiation orirradiation that the shells can absorb and translate into heat. Forexample, for nanoshells formed of a metal such as gold, the wavelengthat which extinction efficiency is largest shifts to longer wavelengthsas core-to-shell ratios increase, i.e. as shell thickness decreases ifthe outer diameter is kept constant. Most relevant, the nanoshells canbe designed such that they absorb radiation energy in the near-infraredspectrum between 650 nm and 900 nm which is permeable for tissue (see,e.g., Oldeburg S. J., et al., Applied Physics Letters; Vol. 75(19):2897-2899; Oldenburg S. J., et al., Chemical Physics Letters 288:243-247(1998)).

The nano-constructs described herein can be delivered to a subject fortreating or ameliorating a vascular condition such as atheroscleroticplaque. Upon delivery, the nano-constructs can reach the target site viapassive targeting or active targeting. Passive targeting can be achievedby extravasation of the nano-construct through leaky vasculature such asthose present in atherosclerotic plaque. In some embodiments, the resultof passive targeting can be assessed by the circulation time of thenano-constructs after delivery. Generally, the longer thenano-constructs remain in circulation, the more nano-constructs canreach the target site or target tissue, which sometimes is also referredto as the diseased site or diseased tissue. Therefore, in someembodiments, passive targeting can be enhanced by increasingnano-construct circulation times by rendering the surface of thenano-construct disguisey using a compound such as poly(ethylene glycol).Other compounds that can be used to hide the nano-constructs include,but are not limited to, hyaluronic acid, phosphoryl choline, dextran,dextrose, sulfo betaine, polypyrrolidone, poly(2-hydroxyethylmethacrylate), albumin, poly(acrylic acid), and poly(methacrylic acid)and PVA.

Extravasation of the nano-constructs is also related to the position andnature of the diseased tissue. The capillary walls of tumor vasculatureand the inflamed vasculature of diseased tissue is leaky compared tonormal tissue. In some embodiments, extravasation can be achieved bycirculation of the nano-constructs in the blood stream for a period from10 minutes to 120 hours, more specifically from about 4 hours to 48hours.

In some embodiments, the targeting can be achieved by active targeting.Active targeting can be carried out by attaching a targeting molecule onthe nano-constructs (e.g., nanoshells). Targeting molecules include anypeptide, antibody, or polysaccharide that has affinity to the targettissue or target site (e.g., atherosclerotic plaque). In someembodiments, the targeting molecule can be a surface-conjugated ligandto a receptor on an inflamed endothelium. Some examples of the targetingmolecules are antibodies to CD34, RGD, YIGSR, peptides and antibodies toIIbIIIa, heparin, hyaluronic acid, laminin, collagen, ICAM-1, ICAM-2,ICAM-3, fibrinogen, fibronectin, vitronectin, thrombospondin,osteopontin, integrins, VCAM-1, N-CAM, PECAM-1, IgCAM, folate,oligonucleotide aptamers, selectins, and cadherins.

The result of active targeting can be assessed by measuring the quantityof nano-constructs in the targeted tissue (i.e. vessel wall) versus thequantity administered. Similar to passive targeting, in someembodiments, the result of active targeting can be assessed by thecirculation time of the nano-constructs after delivery. Generally, thelonger the nano-constructs remain in circulation, the morenano-constructs can reach the target site. Therefore, in someembodiments, active targeting mediated by a targeting moiety can beenhanced by increasing nano-construct circulation times by modifying thesurface of the construct using compounds such as poly(ethylene glycol),hyaluronic acid, phosphoryl choline, dextran, dextrose, sulfo betaine,poly(vinyl alcohol) (PVOH), polypyrrolidone, poly(2-hydroxyethylmethacrylate), albumin, poly(acrylic acid), poly(methacrylic acid) andPVA, whereby the organism's immunological processes fail to recognizethe nano-construct as foreign.

Active targeting of the nano-constructs is also related to the positionand nature of the diseased tissue. Nano-constructs can reach diseasedtissue, which is highly vascularized, by systemic administration.Diseased tissue protected by the blood-brain barrier, which can preventpenetration of the nano-constructs, could be more advantageouslyaccessed by administration into cerebro-spinal fluid. If a highconcentration of nano-constructs is desired in the vessel wall of aportion of vascular system, then local delivery using a catheter may besuitable. Some target tissues such as the eye or prostate can beaccessed externally by direct injection. In some embodiments, activetargeting can be achieved by circulating the nano-constructs in theblood stream for a period from 10 minutes to 120 hours, morespecifically from about 4 hours to 48 hours.

For those nano-constructs that include bioactive agents, the bioactiveagent can be included in the core material in the form ofcore-material-drug matrix. Alternatively, the bioactive agent can beincluded in a substrate to which the nano-construct described herein isconjugated. For example, the substrate can be a nano- or micro-particleor capsule including the bioactive agent. The heat generated from thenano-construct can cause the bioactive agent to release from thesubstrate. The substrate to which the nano-construct is conjugated canbe formed of the same of different material of the polymeric corematerial of the nano-construct. In some embodiments, the substrate is aself-assembled molecule such as liposomes containing phospholipids,micelles, or polymersomes. Examples of such self-assembled moleculesinclude, but are not limited to, a liposome such as a small unilamellarvesicle (SUV), a large unilamellar vesicle (LUV), a polymersome, orhybrid vesicle comprising a polymer constituent(s). vesicle (LUV), apolymersome, or hybrid vesicle comprising a polymer constituent(s).Finally, the bioactive agent can be included in the shell of thenano-construct. Those of ordinary skill in the art recognize that thesevarious locations for the bioactive agent are not exclusive. Thus, insome embodiments the bioactive agent can be present in any combinationof core, substrate, or shell.

Polymeric Core Materials

The core material can be any polymeric material. Preferably, the coresubstrate can be formed of a material that comprises a biodegradablepolymer. Also, it is preferable for the core polymeric material to havedielectric properties. In some embodiments, the core material can be anon-degradable polymer. As used herein, a degradable polymer is apolymer having a backbone that comprises at least one degradable linkageor grouping in the backbone, and a non-degradable polymer is a polymerhaving a backbone that lacks a backbone degradable linkage or grouping.Degradable linkages or groupings include a bond that can be cleaved byhydrolysis or enzymatic cleavage. An example of a degradable linkage orgrouping is an ester linkage. An example of the non-degradable polymersis a polymer formed of vinyl monomers.

Representative polymeric core materials include poly(ester amide),polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalkanaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyphosphazenes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, vinyl halide polymers andcopolymers, such as polyvinyl chloride, polyvinyl ethers, such aspolyvinyl methyl ether, polyvinylidene halides, such as polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics,such as polystyrene, polyvinyl esters, such as polyvinyl acetate,copolymers of vinyl monomers with each other and olefins, such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. poly(ethylene oxide-co-lactic acid)(PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,phosphoryl choline, choline, poly(aspirin), polymers and co-polymers ofhydroxyl bearing monomers such as 2-hydroxyethyl methacrylate (HEMA),hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, PEGacrylate (PEGA), PEG methacrylate,2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, dextran, dextrin, hyaluronic acid, fragments andderivatives of hyaluronic acid, heparin, fragments and derivatives ofheparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide,elastin, or combinations thereof.

In some embodiments, the polymeric core material can exclude any one ormore of the aforementioned polymers.

As used herein, the terms poly(D,L-lactide), poly(L-lactide),poly(D,L-lactide-co-glycolide), and poly(L-lactide-co-glycolide) can beused interchangeably with the terms poly(D,L-lactic acid), poly(L-lacticacid), poly(D,L-lactic acid-co-glycolic acid), or poly(L-lacticacid-co-glycolic acid), respectively.

In some embodiments, the core material can include ferromagnetic ormagnetic ceramic particles.

Bioactive Agents

The nanoshells described herein can include one or more bioactiveagent(s), which can be therapeutic, prophylactic, or diagnosticagent(s). These agents can have anti-proliferative or anti-inflammatoryproperties or can have other properties such as antineoplastic,antiplatelet, anti-coagulant, anti-fibrin, antithrombogenic,antimitotic, antibiotic, antiallergic, antifibrotic, and antioxidant.The agents can be cystostatic agents, agents that promote the healing ofthe endothelium such as NO releasing or generating agents, agents thatattract endothelial progenitor cells, agents that promote theattachment, migration and proliferation of endothelial cells (e.g.,natriuretic peptides such as CNP, ANP or BNP peptide or an RGD or cRGDpeptide), while impeding smooth muscle cell proliferation. Examples ofsuitable therapeutic and prophylactic agents include synthetic inorganicand organic compounds, proteins and peptides, polysaccharides and othersugars, lipids, and DNA and RNA nucleic acid sequences havingtherapeutic, prophylactic or diagnostic activities. Some other examplesof the bioactive agent include antibodies, receptor ligands, enzymes,adhesion peptides, blood clotting factors, inhibitors or clot dissolvingagents such as streptokinase and tissue plasminogen activator, antigensfor immunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides, small interfering RNA (siRNA), small hairpinRNA (shRNA), aptamers, ribozymes and retroviral vectors for use in genetherapy. Examples of anti-proliferative agents include rapamycin and itsfunctional or structural derivatives,40-O-(2-hydroxy)ethyl-rapamycin(everolimus), and its functional orstructural derivatives, paclitaxel and its functional and structuralderivatives. Examples of rapamycin derivatives include40-epi-(N1-tetrazolyl)-rapamycin (ABT-578),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.Examples of paclitaxel derivatives include docetaxel. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatory agents include tacrolimus,dexamethasone, clobetasol, or combinations thereof. Examples ofcytostatic substances include angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g. Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g. Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.). An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, pimecrolimus, imatinib mesylate,midostaurin, bioactive RGD, SIKVAV peptides, elevating agents such ascANP or cGMP peptides, and genetically engineered endothelial cells. Theforegoing substances can also be used in the form of prodrugs orco-drugs thereof. The foregoing substances also include metabolitesthereof and/or prodrugs of the metabolites. The foregoing substances arelisted by way of example and are not meant to be limiting. Other activeagents which are currently available or that may be developed in thefuture are equally applicable.

The dosage or concentration of the bioactive agent required to produce afavorable therapeutic effect should be less than the level at which thebioactive agent produces toxic effects and greater than non-therapeuticlevels. The dosage or concentration of the bioactive agent can dependupon factors such as the particular circumstances of the patient, thenature of the trauma, the nature of the therapy desired, the time overwhich the administered ingredient resides at the vascular site, and ifother active agents are employed, the nature and type of the substanceor combination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

Methods of Forming Nanoshells

Nanoshells can be formed on a core material using established methods.For example, U.S. Pat. No. 6,699,724 describes forming conductingnanoshells on a non-conducting core. The size and thickness of thecore/shell can be tuned so that the particles can absorb light with adesired wavelength. Biomolecules such as proteins or peptides can beattached to the nanoshells for binding to a specific tissue.

U.S. Pat. No. 6,685,986 describes a method of forming metal nanoshellsupon a core substrate. The nanoshells can be formed of a metal such asgold or a conducting polymer. The core substrate can be particles ofsilicon dioxide, titanium dioxide, alumina, zirconia, poly(methylmethacrylate) (PMMA), polystyrene, gold sulfide, macromolecules such asdendrimers, semiconductors such as CdSe, CdS, or GaAs. The particles canfurther have polyvinyl alcohol (PVA), latex, nylon, Teflon, acrylic,Kevlar, epoxy, or glasses. Some other references, for example, U.S.application publication Nos. 2003/0164064, 2002/0061363, 2002/0187347,2002/0132045, and 2005/0056118, also describes various methods offorming metal nanoshells on a core substrate. Formation of partialnanoshells can be according to the method described in, for example,U.S. Pat. No. 6,660,381.

In some embodiments, the nanoshells can be formed via metal colloidalnanoparticles such as colloidal gold nanoparticles. For example,colloidal gold nanoparticles of 3-4 nm size can assemble on nanoparticlesurfaces functionalized by amine groups. These nanoparticles act asnucleation sites, and when a gold salt is present in a reducingenvironment, a solid gold shell can be formed around this type ofnanosize template such as a nanosphere.

In some embodiments, polymeric nanoparticles such as commerciallyavailable polystyrene particles modified at their surface to presentamine groups may be used as a template for gold nanoshells. Aminefunctionality can be placed onto these polymers by a variety oftechniques. For example, polymeric surface can be modified to have aminefunctionality via plasma treatment in the presence of ammonia orhydrazine. This plasma process can be carried out on preformednanoparticles by agitating them in a plasma reactor. Amino groups canalso be incorporated into the end-groups of a polymer (e.g., abiodegradable polymer), if the initiator contains both a hydroxyl groupand an amino group protected by a carbobenzoxy group or at-butoxycarbonyl group, and this initiator is used to make abiodegradable polymer by ring opening polymerization, such aspoly(L-lactide) or polyglycolide. After the polymerization, theprotecting group can be removed, liberating the amino group. Polymericmethacrylates can be made with amino groups by using a monomer such asN-(3-aminopropyl)methacrylamide. A copolymer with other monomers suchhas butyl methacrylate or methyl methacrylate can be made. In someembodiments, a dispersion or emulsion polymerization process can be usedto form monodisperse nanoparticles with surface amino groups (see, e.g.,Ramos; Jose, Forcada; Jacqueline. Polymer 47(4):1405 (2006); Ramos;Jose, Forcada; Jacqueline, Polymer Chemistry 43 (17):3878 (2005);Prakash, G. K. et al., J. of Nanoscience and Nanotechnology 5(3):397(2005); and Musyanovych, Anna; Adler, Hans-Jurgen Organic Chemistry IIIMacromolecular Society, 21(6):2209 (2005).

In some embodiments, the nanoshells can be formed viathiol-group-facilitated nanoparticle assembling. For example,biodegradable poly(propylene sulfide) can be produced in nanoparticleform as shown by Annemie Rehor (Ph. D. thesis, Swiss Federal Instituteof Technology, Zurich, 2005). This polymer has thiol end-groups from thepolymerization, which can be maximized in number by exposing thenanoparticles to reducing conditions.

In some embodiments, the nanoshells can be modified to include atargeting molecule. The target molecule can be any peptides orantibodies such as ligands for receptors on an inflamed endothelium.Examples of such targeting molecules include, but are not limited to,antibodies to CD34, RGD, YIGSR, peptides and antibodies to IIbIIIa,heparin, hyaluronic acid, laminin, collagen, ICAM-1, ICAM-2, ICAM-3,fibrinogen, fibronectin, vitronectin, thrombospondin, osteopontin,integrins, VCAM-1, N-CAM, PECAM-1, IgCAM, folate, oligonucleotideaptamers, selectins, and cadherins.

Attachment of targeting molecule to nanoshells can be achieved byestablished methods. The targeting molecule can be attached to thenanoshell via covalent bonding or non-covalent interaction. Non-covalentinteraction can be based on ionic interaction, hydrogen bonding or othertype of interaction. For example, after formation of the gold nanoshell,molecules functionalized with a thiol group can be used to modify thenanoshell surface for targeting of the nanoshell, or to disguise thenanoshell surface. Thiol-terminated molecules have been shown toself-assemble on gold surfaces. For example, thiol-terminatedpoly(ethylene glycol) (PEG) having a molecular weight of about 200Daltons to 10,000 Daltons, preferably between 500 Daltons to about 2,000Daltons can be used to disguise the nanoshell surface. The other end ofthe PEG chain can be functionalized with a targeting molecule such as apeptide or an antibody to target the nanoshell to specific tissue withinthe body.

In some embodiments, the targeting molecule can be attached to ananoshell via a spacer. A spacer molecule can be a short-chain alkylgroup such as a C1-C20 alkyl, C3-C20 cycloalkyl, poly(ethylene glycol),poly(alkylene oxide). Other spacer molecules include dextran, dextrose,heparin, poly(propylene sulfide), hyaluronic acid, peptides, DNA, PVAand PVP.

Method of Use

The nano-constructs provided herein can be delivered or administered toa subject via any established mode of delivery. For example, thenano-constructs can be delivered by systemic delivery such as systemicinjection. In some embodiments, the nano-constructs can be administeredby local delivery such as direct injection. For disorders of thevascular system, the nano-constructs may be administered bycatheter-based devices. These would include single and dual needleinjection catheters, porous balloon catheters, balloon catheters withjets, and double balloon catheters. In general, the nano-constructs ofthis invention do not rely on any particular delivery method.

Upon delivery to the target tissue, an energy source can be applied tothe nano-constructs. The nano-constructs can then absorb the energy andconvert it or translate it to heat so as to warm or ablate the diseasedtissue. The energy source can be in any form capable of reaching thenano-constructs and being absorbed and converted by the nano-constructsinto heat. In some embodiments, the energy source can be applied throughexternal radiation or through a catheter-based guidance system.

In some embodiments, the energy source is an electromagnetic radiationhaving a wave length from 500 nm to 1500 nm. For example, the energysource can be a near infrared radiation.

In some embodiments, the energy source is a fluctuating electromagneticfield. Such electromagnetic field can have a frequency from 1×10⁶ Hz to6×10¹⁴ Hz. In some embodiments, the electromagnetic field can have afrequency of 700 nm to 1300 nm where optical transmission is optimal(Welch A.; van Gemert, M. e. Optical-Thermal Response of LaserIrradiated Tissue, Plenum Press: New York, 1995).

In some embodiments, the energy source can be applied to thenano-constructs by a catheter-based fiber-optic. The localization ofplaque can be imaged prior to the procedure or during the procedure byinterrogation with an attenuated radiation. For example, the plaque maybe imaged by optical coherence tomography using a wavelength of 1300 nm(Meissner O. A., et al. J Vasc Interv Radiol 2006; 17: 343-349) orintravascular ultrasound (Colombo et al., Circulation, 91:1676-88(1995)). This same wavelength could then be used to apply energy to thenano-constructs after they are administered.

The nano-construct described herein can be used to treat, prevent orameliorate a medical condition. Such a medical condition can be, e.g., atumor or nephropathic kidney. In some embodiments, such a site can be asite of atherosclerosis. Other medical conditions treatable usinginvention processes or nanoconstructs include vulnerable plaque, diffuseatherosclerotic disease, diabetic retinopathy, aneurysm, anastomotichyperplasia, claudication, chronic total occlusion, dysfunctionalendothelium, recurring thrombus, fibrin accumulation, or combinations ofthese.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A nano-construct comprising (a) a core material comprising a polymer,(b) a nanoshell formed around the core material, and (c) optionally abioactive agent, wherein the polymer is a degradable polymer ornon-degradable polymer a non-degradable polymer selected frompoly(N-(3-aminopropyl)methacrylamide) or a copolymer ofN-(3-aminopropyl)methacrylamide, or combinations of these.
 2. Thenano-construct of claim 1 wherein the nanoshell comprises gold.
 3. Thenano-construct of claim 2 wherein the gold nanoshell has a thicknessbetween about 5 and about 25 nm.
 4. The nano-construct of claim 1wherein the core material has a size in the range between about 150 nmto about 2000 nm.
 5. The nano-construct of claim 4 wherein the goldnanoshell surrounding the core material is porous to the optionalbioactive agent.
 6. The nano-construct of claim 1 wherein the nanoshellis comprises iron, iron based alloys, magnesium, magnesium alloys, zinc,calcium, tungsten, alloys based on these metals, or combinationsthereof.
 7. The nano-construct of claim 1 wherein the nanoshellcomprises an electrically conductive, organic material.
 8. Thenano-construct of claim 1 wherein the nanoshell comprises graphite or aconductive polymer.
 9. The nano-construct of claim 1 wherein thenanoshell comprises poly(L-lactide), polyhydroxyalkanoate,polycaprolactone, or combinations thereof.
 10. The nano-construct ofclaim 1 further comprising a substrate that includes the optionalbioactive agent.
 11. The nano-construct of claim 10 wherein thesubstrate is a small unilamellar vesicle (SUV) encapsulating thebioactive agent.
 12. The nano-construct of claim 10 wherein thesubstrate is a liposome, polymersome, or hybrid vesicle.
 13. Thenano-construct of the claim 1 wherein the core material furthercomprises ferromagnetic or magnetic ceramic particles.
 14. Thenano-construct of claim 1 wherein the core material comprises a peptide,a protein, or a combination of these.
 15. The nano-construct of claim 1,further comprising a targeting molecule on the surface of thenano-construct.
 16. The nano-construct of claim 15 wherein the targetingmolecule is a surface-conjugated ligand for receptors on an inflamedendothelium.
 17. The nano-construct of claim 1 in a formulation suitablefor systemic delivery or local delivery into a human being.
 18. Thenano-construct of claim 17 wherein the systemic delivery is injection.19. The nano-construct of claim 17 wherein the local delivery isdelivery by a device comprising a catheter.
 20. The nano-construct ofclaim 1 wherein the optional bioactive agent is paclitaxel, docetaxel,estradiol, 17-beta-estradiol, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin(everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs,or combinations of these.
 21. A method comprising: forming a nanoshellaround a polymeric core material, wherein the polymeric core material isa degradable polymer or a non-degradable polymer selected frompoly(N-(3-aminopropyl)methacrylamide) or a copolymer ofN-(3-aminopropyl)methacrylamide, or combinations of these.
 22. Themethod of claim 21 wherein the core material encapsulates at least onebioactive agent.
 23. The method of claim 21 wherein the nanoshell isporous.
 24. The method of claim 21 further comprising connecting thenano-construct to a substrate.
 25. The method of claim 21 wherein thesubstrate comprises a self-assembled structure.
 26. The method of claim21 wherein the nanoshell comprises gold and has a thickness betweenabout 5 and about 25 nm.
 27. The method of claim 21 wherein thenanoshell consists essential of gold and has a thickness between about 5and about 25 nm.
 28. The method of claim 21 wherein the core materialhas a size between about 150 nm and about 200 nm.
 29. The method ofclaim 21 wherein the core material comprises a peptide, a protein, or acombination of these.
 30. The method of claim 21 wherein thenano-construct comprises a targeting molecule on the surface of thenano-construct.
 31. The method of claim 29 wherein the targetingmolecule is surface-conjugated ligands against receptors on an inflamedendothelium.
 32. The method of claim 21 wherein the nano-construct is ina formulation suitable for systemic delivery or local delivery into ahuman being.
 33. The method of claim 31 wherein the systemic delivery isinjection.
 34. The method of claim 31 wherein the local delivery isdelivery by a device comprising a catheter.
 35. The method of claim 22wherein the bioactive agent is paclitaxel, docetaxel, estradiol,17-beta-estradiol, nitric oxide donors, super oxide dismutases, superoxide dismutases mimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO), tacrolimus, dexamethasone, rapamycin, rapamycinderivatives, 40-O-(2-hydroxy)ethyl-rapamycin(everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs,or combinations of these.
 36. A method of treating, preventing, orameliorating a medical condition, comprising delivering to a diseasesite in the body of a human being in need of treatment thenano-construct of claim 1, and causing the nano-construct to release thebioactive agent.
 37. The method of claim 36 wherein the causingcomprises irradiating the nano-construct an irradiation, and wherein thenano-construct converts the radiation into heat.
 38. The method of claim37 wherein the irradiation uses a near infrared (NIR) electromagneticradiation transmitted through a catheter-based fiber-optic.
 39. Themethod of claim 36 wherein the radiation is electromagnetic and isapplied outside the body of the subject.
 40. The method of claim 36wherein the delivering comprises allowing the nano-constructs toextravasate through leaky vasculature in the target tissue.
 41. Themethod of claim 36 wherein the nano-construct comprises targetingmolecules on the surface of the nano-construct.
 42. The method of claim39 wherein the targeting molecule comprises surface-conjugated ligandsagainst receptors on an inflamed endothelium.
 43. The method of claim 38wherein the nano-construct comprises a surface-disguising compound onthe surface of the nano-construct that increases the circulation time ofthe nano-construct.
 44. The method of claim 38 wherein thesurface-disguising compound comprises poly(ethylene glycol).
 45. Themethod of claim 38 wherein medical condition is one or more of ofatherosclerosis, tumor, a nephrosis, vulnerable plaque, diffuseatherosclerotic disease, diabetic retinopathy, aneurysm, anastomotichyperplasia, claudication, chronic total occlusion, dysfunctionalendothelium, recurring thrombus, or fibrin accumulation.
 46. The methodof claim 36 wherein the bioactive agent comprises one or more ofpaclitaxel, docetaxel, estradiol, 17-beta-estradiol, nitric oxidedonors, super oxide dismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives,40-O-(2-hydroxy)ethyl-rapamycin(everolimus),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578), γ-hiridun, clobetasol,pimecrolimus, imatinib mesylate, or midostaurin, or prodrugs, co-drugs,or combinations of these.